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Title: Integrated analysis reveals that STAT3 is central to the crosstalk between HER/ErbB receptor signaling pathways in human mammary epithelial cells

Human epidermal growth factor receptors (HER, also known as ErbB) drive cellular proliferation, pro-survival and stress responses by activating several downstream kinases, in particular ERK, p38, JNK (SAPK), the PI3K/AKT, as well as various transcriptional regulators such as STAT3. When co-expressed, first three members of HER family (HER1-3) can form homo- and hetero-dimers. Based on the considerable evidence which suggest that every receptor dimer activates intracellular signaling pathways differentially, we hypothesized that the HER dimerization pattern is a better predictor of downstream signaling than the total receptor activation levels. We validated our hypothesis using a combination of model-based analysis to quantify the HER dimerization patterns and multi-factorial experiments where HER dimerization patterns and signaling crosstalk were rationally perturbed. We have measured the activation of HER1-3 receptors and of the sentinel signaling proteins ERK, AKT, p38, JNK, STAT3 as a function of time in a panel of human mammary epithelial (HME) cells expressing different levels of HER1-3 stimulated with various ligand combinations. Our analysis using multiple ways of clustering the activation data has confirmed that the HER receptor dimer is a better predictor of the signaling through p38, ERK and AKT pathways than the total HER receptor expression and activation levels.more » Targeted inhibition studies to identify the causal effects allowed us to obtain a consensus regulatory interaction model, which revealed that STAT3 occupies a central role in the crosstalk between the studied pathways.« less
Authors:
 [1] ;  [1] ;  [1] ;  [2]
  1. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Computational Biology and Bioinformatics Group
  2. Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Computational Biology and Bioinformatics Group; Washington State Univ., Pullman, WA (United States). School of Chemical Engineering and Bioengineering; Washington State Univ., Pullman, WA (United States). School of Electrical Engineering and Computer Science
Publication Date:
OSTI Identifier:
1184915
Report Number(s):
PNNL-SA--100045
Journal ID: ISSN 1742-206X; MBOIBW; 400412000
Grant/Contract Number:
AC05-76RL01830; AC06-76RL01830; 5R01GM072821-07
Type:
Accepted Manuscript
Journal Name:
Molecular BioSystems
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 1742-206X
Publisher:
Royal Society of Chemistry
Research Org:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US)
Sponsoring Org:
USDOE; National Inst. of Health (NIH)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES